Targeting homologous recombination repair to potentiate fluoroquinolone efficacy in Mycobacterium abscessus
Shuai Wang, Md Shah Alam, Buhari Yusuf, Jingran Zhang, Ziwen Lu, Xiaofan Zhang, H. M. Adnan Hameed, Mst. Sumaia Khatun, Chunyu Li, Lijie Li, Aleksey A. Vatlin, Aweke M. Belachew, Xirong Tian, Yamin Gao, Cuiting Fang, Rogers P. Zhang, Jun Li, Xinyue Wang, Liqiang Feng, Li Wan, Tianyu ZhangImpact statement
Fluoroquinolones (FQs) are important for treating fast‐growing mycobacterial infections; however, their efficacy can be limited by intrinsic resistance and the emergence of acquired resistance. FQs induce lethal DNA double‐strand breaks (DSBs) by targeting topoisomerases. Through a transposon screen in Mycobacterium abscessus , we identified that disruption of adnB , a homologous recombination (HR) gene, markedly sensitized the pathogen to FQs. Subsequent study showed that deleting core HR components ( adnB , recO , recA , recR , and ruvB ) increased FQs' susceptibility, while other DSB repair pathways (single‐strand annealing or non‐homologous end joining) had no effect, demonstrating a unique reliance on HR for FQs' tolerance. Complementation with native or its homolog genes restored the resistance phenotype, indicating a conserved HR‐dependent tolerance mechanism in M . abscessus . In a murine model, genetic HR abrogation significantly improved FQs' therapeutic efficacy. These results highlight HR repair as a potential therapeutic target to potentiate FQs' activity and combat drug resistance in M . abscessus infections.